Laryngeal endocrinomas (carcinoids and relevant neoplasms): analysis of 278 reported cases.

This study was carried out to provide extensive information obtained from statistical analysis of laryngeal endocrinomas for the use of investigators working in this particular research field. A total of 278 patients with both typical and atypical varieties of carcinoids, and with small/oat cell carcinomas (SCC/OCC) exhibiting a confirmed endocrine nature were statistically evaluated, and the significance in various clinicopathologic aspects among these three types of such endocrine neoplasms of the larynx was compared. A statistically significant difference between two groups of typical carcinoid and atypical variety was evident only in a few items such as rates of metastases, positive CEA, and multisecretory activity, while a significant difference between the carcinoid groups and SCC/OCC group was demonstrated in numerous areas, among others, e.g. 1) in the overall rates of metastases and at the sites of involvement, 2) in Grimelius argyrophilia, 3) in immunohistochemical demonstration of positive chromogranin, CEA, calcitonin and multisecretory activity, and 4) in the 5-year survival rates. Such a definite difference between the carcinoid groups and SCC/OCC group suggested an apparently different characteristic nature present between these two series of neoplasms. The necessity of an international agreement regarding diagnostic criteria for typical carcinoids and atypical varieties was in particular emphasized from a viewpoint of an exceptionally high incidence of laryngeal atypical carcinoids in comparison to such neoplasms in other organs.

Gut-endocrinomas (carcinoids and related endocrine variants) of the uterine cervix: an analysis of 205 reported cases.

This study was carried out statistically to evaluate the present situation of carcinoids and related endocrine variants in the uterine cervix. A total of 205 patients who had been reported on in world-wide literature were divided into two groups; one, as a carcinoid group, consisting of 81 patients with carcinoids, 49 typical and 32 atypical, and the others, as an endocrine carcinoma (ECC) group, including 124 patients with other remaining endocrine carcinomas variously expressed up to date. A statistical comparison in multiple factors was attempted between these two groups. A statistically significant difference between them was demonstrated in immunochemistry for chromogranin (p<0.05), serotonin (p<0.01), and CEA (p<0.01), but not regarding average age, clinical manifestations, tumor-size categorization, rates of metastases, sites of metastases, argyrophilia or argent affinity, and postoperative five-year survival rates, though the latter disclosed a statistically significant difference (p<0.05) only between the two groups of typical and atypical carcinoids. The results of analysis in the present study disclosing no statistically significant differences in various aspects between the two groups of carcinoids and the remaining endocrine carcinomas strongly suggest that the considerable extent of confusion produced by various different types of terminology for carcinoids and related endocrine variants should be solved by extensive evaluation and discussion on an international scale, and that diagnostic criteria and simplified classification acceptable for these neoplasms are to be established not only for those of the uterine cervix but also for those of all other organs including the digestive system based on a universally acceptable concept for these neoplasms originating in non-endocrine organs.

Gut-endocrinomas (carcinoids and related endocrine variants) of the breast: an analysis of 310 reported cases.

The purpose of this study was to analyze the present status of gut-endocrinomas (carcinoids and related endocrine variants) of the breast, an extremely rare site for primary growth of such neoplasms, and to provide precise and reliable information concerning these neoplasms on varying clinicopathological aspects for investigators engaged in relevant research fields. A total of 310 cases presented in this analysis consisted of 196 carcinoids, 102 typical and 94 atypical, and 114 related endocrine variants; in the last group, the expression of "breast carcinoma with (neuro-) endocrine differentiation" was often used without referring to the term "carcinoid." A statistical evaluation was performed on most occasions based on a comparison among three groups of typical carcinoids, atypical carcinoids and related endocrine variants, or between the former two series of carcinoids and the third series of endocrine carcinomas. Statistically significant differences between the groups of carcinoids and endocrine carcinomas were recognized in terms of average age, tumor size categories of < or = 20 mm and 21-50 mm, rates of metastases, and positive neuron-specific enolase (NSE) immunohistochemistry. Contrary to our expectations no statistically significant difference between these two groups was evident in terms of overall average tumor size, Grimelius argyrophilia for endocrine nature, or postoperative 5-year survival rates in curative resection cases. It seems important to establish more precise diagnostic criteria for "endocrine carcinomas" from the viewpoint of a certain possibility that some of these neoplasms may belong to the atypical carcinoid group.

Carcinoids of the ovary: an analysis of 329 reported cases.

This evaluation was undertaken to supply precise and reliable detailed information to investigators actively working in carcinoid and related gynecological research fields. A statistical evaluation was performed on 329 cases of ovarian carcinoid registered in the Niigata Registry where world-wide information of gut-pancreatic endocrinomas has been maintained by a computer-analyzing system. Cases without individual identification or those recorded in groups were excluded. The evaluation was carried out mainly by a comparison between two groups of cases with cystic teratoma/dermoid (Group A) and those without such lesions (Group B). The former group consisted of 189 cases (57.4%) and the latter of 140 (42.6%). Statistically significant differences between these two groups were recognized in tumor size (44.7 mm vs 89.8 mm), rate of metastases (5.8% vs 22.1%), rate of hepatic involvement (2.1% vs 15.0%), incidence of associated carcinoid syndrome (13.8% vs 22.9%) and 5-year survival rate (93.7% vs 84.0%). Insular type and trabecular type carcinoids were recorded at an almost equal rate of one fourth ranging between 22% and 26% in either group. Another significant difference in the incidence of carcinoid syndrome was evident between the series of insular type and trabecular type carcinoids (38.9% vs 7.8%). The present evaluation on ovarian carcinoids disclosed definite, statistically significant differences in various clinical and pathophysiologic aspects between Group A and Group B, as well as between insular type and trabecular type histologic structures.

Evaluation of 342 cases of mediastinal/thymic carcinoids collected from literature: a comparative study between typical carcinoids and atypical varieties.

This study is aimed to provide extensive and useful information based on an analysis of a large and reliable series of cases regarding mediastinal/thymic carcinoids, both typical and atypical. It also serves to assist investigators to improve their research activities in this particular field. In the present study, 342 patients (3.8%) with mediastinal/thymic carcinoids from amongst a total series of 8,970 patients with carcinoids, registered in the Niigata Registry for gut-pancreatic endocrinomas, were analyzed to clarify their detailed clinicopathological characteristics. Added to an analysis of mediastinal/thymic series including a comparison between typical and atypical carcinoid varieties, another comparative study was performed between the present series and a bronchopulmonary series. Mediastinal/thymic carcinoids may be briefly characterized by 1) no significant difference in major factors statistically demonstrable between typical carcinoids and atypical varieties, 2) a male preponderance, 3) difficult (delayed) preoperative diagnosis, 4) a high rate of metastasis, 5) a large tumor size on average (delayed detection), 6) a low rate of the carcinoid syndrome, 7) a high rate of association of the Cushing syndrome, and 8) low postoperative survival rates.

Bronchopulmonary carcinoids: An analysis of 1,875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties.

This study was undertaken to provide investigators working in this particular research field with extensive and useful basic information based on an analysis of a large reliable series of cases regarding tracheal and bronchopulmonary carcinoids and their atypical varieties. A statistical evaluation was carried out which included a total of 1,875 patients with tracheal and bronchopulmonary carcinoids; these were divided into two series, one of 1,595 patients with typical carcinoids and the other of 280 with atypical varieties. These two series were compared regarding various aspects, which included the male to female ratio, age distribution, clinical manifestations, successful preoperative diagnosis, diagnostic accuracy of representative procedures, sites of involvement, tumor size distribution, metastases, carcinoid syndrome, serotonin activity in patients with or without the syndrome, immunohistochemistry, electron microscopy, and postoperative prognosis of the patients. The comparative analyses between the two series disclosed statistically significant differences (p<0.01) regarding various viewpoints; among others, such a difference was proved in the average age, sites of involvement in the lung (central or peripheral), rates and sites of metastases, adrenocorticotrophic hormone (ACTH) production, the association rate of the carcinoid syndrome, and postoperative 5-year and 10-year survival rates (93.3% and 82.1% for the typical carcinoid series versus 68.8% and 58.6% for the atypical variety series: p<0.0001). The postoperative 5-year and 10-year survival rates in the other two groups of patients with or without metastases were likewise calculated and showed a statistically significant difference (72.8% and 52.8% for the former versus 98.3% and 95.4% for the latter: p<0.0001).

Carcinoid syndrome: a statistical evaluation of 748 reported cases.

No statistical evaluation of patients with carcinoid syndrome in a reliable number of cases has been available in the past 35 years. To update our knowledge about the syndrome, we have evaluated from various clinicopathologic viewpoints a large series of patients with the syndrome reported up to date. The data of 748 patients with the syndrome were collected from 8876 carcinoid patients reported in the literature and analyzed by the Gut-Pancreatic Endocrinoma Analyzing System (the Niigata Registry). The results are summarized as follows. 1) The patients with the syndrome had a tendency to be older than those without it. 2) The incidence of the syndrome was 8.4% of 8876 carcinoid patients. 3) Serotonin activities were extremely high in patients with the syndrome as compared to those without it (91.7% versus 26.6%). 4) The rate of metastases was higher in patients with the syndrome than in those without it (84.8% versus 29.2%), and higher in the liver than in lymph nodes among patients with the syndrome (73.4% versus 37.4%). 5) Flushing and carcinoid heart as most specific clinical manifestations of the syndrome were recorded at 78.3% and 17.4%, respectively. 6) The 5-year survival rate after resection of primary lesions was 76.0% of 304 patients with the syndrome, lower in patients with digestive carcinoids than in those with extradigestive lesions (67.2% versus 88.7%). It is expected that the results obtained in the present evaluation on patients with carcinoid syndrome will provide investigators active in this specialized field with useful and extensive information for their future activities.

A classification of problems regarding gut endocrinomas (carcinoids and relevant neoplasms).

In the field of gut endocrinomas (carcinoids and relevant neoplasms), several classifications have been internationally accepted and utilized at varying frequency. The basis of the concepts regarding gut endocrinomas from which these classifications have been proposed were drawn from the different aspects. These included embryology, histologic growth patterns, histochemistry including silver impregnations, electron microscopic morphology of endocrine secretory granules, endocrine cell types and histologic morphology along with functional characteristics, supplemented by immunohistochemical features. Due to continuous progress being made in this particular field of research and the many new discoveries made by pioneering investigators, the concepts of gut endocrinomas have been modified and revised during such long history of the research activities. This study aims to re-evaluate these classifications in relation to the concepts of gut endocrinomas, and to select and supply rearranged classifications that may be easily utilized for practical purposes. This study also proposes a comprehensive overview of histogenesis in the gut endocrinoma group. This consists of typical carcinoids and their atypical variants taken in relation to the carcinomatous group including ordinary carcinomas and their variants with endocrine elements. Special emphasis is given to the point that there is a gradual transition, one without a definite boundary between these tumors.

Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas.

Somatostatin is known to inhibit the secretory release of other peptide hormones. Somatostatinomas associated either with or without somatostatinoma (inhibitory) syndrome are rare neoplasms among gut-pancreatic endocrinomas. Collected from international literature, this study aimed to perform a statistical analysis on 173 patients with somatostatinoma/inhibitory syndrome. The evaluation further attempted to provide investigators in this particular field of research with extensive and precise information on the present situation of somatostatinoma. The 173 patients consisted of 81 with pancreatic somatostatinomas and 92 with extrapancreatic somatostatinomas. Most of the latter were found to have originated in the duodenum and may be termed as carcinoid somatostatinoma. Where data were considered to be adequate, a comparative study was carried out between two groups, pancreatic and duodenal, each consisting of 81 patients. A statistically significant difference between these two groups was found in the incidence of inhibitory syndrome (18.5% versus 2.5%) and von Recklinghausen's disease (1.2% versus 43.2%), large size of tumor (>20 mm) (85.5% versus 41.4%), multisecretory activities (33.3% versus 16.3%), and presence of psammoma bodies (2.5% versus 49.4%). There was no statistically significant difference in the rate of metastases and malignancy between the two groups. The average postoperative 5-year survival rate was 75.2% in 90 patients overall, 59.9% in 44 with metastases and 100.0% in 46 without metastases. Compared with the other pancreatic endocrinomas, including PPomas, glucagonomas, vipomas, gastrinomas, and insulinomas, somatostatinomas were characterized by the low rate of the relevant syndrome and multiple endocrine neoplasia syndrome type 1. There was a low rate of multiplicity, and a high incidence of psammoma bodies in the duodenal group particularly with von Recklinghausen's disease. A high rate of malignancy was recorded, resulting in a low postoperative survival rate of patients with metastases. In conclusion, somatostatinomas exhibited characteristic features quite different from those of the other pancreatic endocrinomas regarding multiple points.

The gastrinoma/Zollinger-Ellison syndrome: statistical evaluation of a Japanese series of 359 cases.

The diagnostic modalities and management of gastrinoma/Zollinger-Ellison syndrome (ZES) have been markedly modified and improved over the past 15 years. To evaluate the present status of this disease, in terms of various clinicopathologic features, we collected 359 Japanese cases of gastrinoma/ZES from the literature. We found a decreasing incidence (from 74.7% in 1965-1980 to 34.2% in 1981-1995) of multiple surgeries and a decreasing rate (from 94.3% in 1965-1980 to 83.5% in 1981-1995) of ZES associated with gastrinoma. There was an increasing rate (from 12.6% in 1965-1980 to 48.9% in 1981-1995) of correct preoperative diagnosis. (All these differences were significant; P < 0.01). In 1981-1995, there was a high incidence (51. 1%) of small tumors (20 mm or less) and a high rate (39.5%) of metastases, and a relatively favorable postoperative outcome (10-year survival rate of 63.7%); P < 0.05. The diagnosis and treatment of gastrinoma/ZES have been markedly improved by increased rates of curative surgery, and more favorable postoperative outcomes will be expected in decades to come.

Insulinoma/hypoglycemic syndrome: a statistical evaluation of 1085 reported cases of a Japanese series.

Over the past 25 years and more, very few statistically reliable evaluations dealing with clinicopathologic features of patients with insulinoma and/or hypoglycemic syndrome (HGS), including recently popularized diagnostic modalities, have been published. The aims of this study are threefold: first, to evaluate the clinicopathologic features of patients with insulinoma/HGS from various viewpoints; secondly, to update our knowledge about this subject which has been retained up to date, and thirdly to supply reliable information to investigators working in the specialized field of gut-pancreatic endocrinomas. We collected data from literature on a total of 1085 Japanese patients with insulinoma/HGS and undertook a statistical evaluation. The results are summarized as follows. 1) Association of HGS was recognized in 88.4% of the 1085 patients. 2) Islet B-cell hyperplasia/nesidioblatosis was found in 4.1%; 2.6% in association with insulinoma and 1.6% without it. 3) Patients with small tumors of 20 mm or less comprised 81.1%. 4) The overall rate of metastases was 6.6% (72 patients) and that of malignancy 13.6% (148 patients). 5) Multisecretors immunohistochemically proved were found in 32.4% and multiplicity of tumor growth in 12.6%. 6) The 10-year survival rate after removal of lesions was 90.5% overall; 98.4% in patients with benign lesions and 75.7% in those with malignant tumors. It is expected that the results obtained in the present study will provide extensive and useful information for future investigation.

Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases.

Based on a statistically reliable number of cases reported in international literature, this study aimed to analyze the present status of vipoma/diarrheogenic syndrome (DGS). Another purpose was to supply investigators in the field of pancreatic endocrinology with precise and extensive information for the future analysis and evaluation of this subject and related problems. We obtained a total of 241 patients with vipoma/DGS from the international literature of 179 with intrapancreatic vipomas, 48 with extrapancreatic neurogenic tumors such as ganglioneuroblastomas, ganglioneuromas and neuroblastomas, and 14 with extrapancreatic vipomas of non-neurogenic nature. When data were considered adequate, a comparative study was attempted between the two groups. A statistically significant difference between the two groups with pancreatic vipomas and neurogenic tumors was found in the rate of the associated syndrome (84.4% versus 95.8%: averaging 86.3%), in tumors the size of which was over 20 mm (79.1% versus 100.0%), in the metastases (56.4% versus 29.2%) and rate of malignancy (64.8% versus 33.3%), and in the rate of resection of primary lesions (68.7% versus 87.5%). When compared to nodal metastasis, hepatic involvement was significantly more frequent in the pancreatic vipoma group (4.2% versus 20.8%). Recent trials of adjuvant chemotherapy with somatostatin analogues indicates an effective result of 78.4% exceeding 31.0% when treated with streptozotocin. The 5-year survival rate in 89 effective patients with pancreatic vipomas was 68.5%; 59.6% for 43 of the patients with metastases and 94.4% for 46 of the patients without metastases.

Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases.

Of the rare pancreatic endocrinomas, glu-cagonomas, either with or without diabetico-dermatogenic syndrome (DDS), are probably third in frequency after insulinomas and gastrinomas. This study was carried out to evaluate the present status of glucagonoma/DDS in a statistically reliable number of cases and to provide precise information to investigators actively working in this particular field of research. A total of 407 cases of glucagonoma were collected from the international literature and evaluated according to characteristic clinicopathologic features. Findings were: (1) The incidence of DDS was 57.2% (233/407). (2) The tail of the pancreas was predominantly involved, in 53.7% (213/397). (3) One-third of the tumors (80 of 276 for whom size was recorded; 29.0%) measured 20 mm or less. (4) Metastases occurred in 51.4% (209/407) and malignant tumors in 60.7% (247/407). (5) Multiplicity occurred in 11.8% (48/407), and associated multiple endocrine neoplasia type 1 in 13. 0% (53/407). (6) In the patients with DDS, the rates of hyperglucagonemia, necrolytic migratory erythema, diabetes mellitus, loss of weight, hypo-aminoacidemia, or anemia, as representative constituents of DDS, were all higher than rates in the overall series (P < 0.01). (7) The 10-year survival rate in the 233 patients with DDS was 51.6% in those with metastases and 64.3% in those without metastases (P < 0.001).